CA1036608A - N-(1'-allylpyrrolidinyl-2'-methyl)-2-methoxy-4,5-azimidobenzamide, salts and preparation thereof - Google Patents

N-(1'-allylpyrrolidinyl-2'-methyl)-2-methoxy-4,5-azimidobenzamide, salts and preparation thereof

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CA1036608A
CA1036608A CA221,531A CA221531A CA1036608A CA 1036608 A CA1036608 A CA 1036608A CA 221531 A CA221531 A CA 221531A CA 1036608 A CA1036608 A CA 1036608A
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methoxy
methyl
acid
acetyl
compound
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Jean-Claude Monier
Gerard Bulteau
Jacques Acher
Claude Collignon
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Societe dEtudes Scientifiques et Industrielles de lIle de France SA
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/16—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical

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Abstract

A B S T R A C T
The invention relates to N-(1'-allylpyrrolidinyl-2'-methyl)-2-methoxy-4,5-azimidobenzamide, which is useful as an antiemetic agent and which possesses kataleptic activity.

Description

The present invention relates to N~ allyl-pyrrolidinyl-2'-methyl)-2-methoxy-4,5-azimido~enzamide, its pharmaceutical1y acceptable addition salts with acids, its ammonium quaternary salts, its levogyre and dextrogyre deriva-tives, and methods for its preparation. Furthermore, the : . invention concerns medical compositions comprising the above compound along with common pharmaceutical auxiliary substances.
It was found that the compound of the invention with respect to its pharmacological properties is superior with respect to similar compounds as well as to further compound known and commercially available under the generic name Metoclopramide which is the 4-amino-5-chloro-N-2-(diethylamino-ethyl)-2-methoxybenzamide.
The structure of the compound of the present invention may be illustrated by three tautomerlc forms:

CO-NH-CH2 ~ CO-NH-CH2 ~ ; ~

~ OCH3 lH CH~=C~ HN ~ CH3 CH2-CH-CH2 N H N - - N ~/

~ , /~ , , CO-NH-CH2 ~ N ~ `~
~ OCH3 CH2-cH-CH2 ~ ~:

N ~1 ;;
Hl - N
The novel compound of the present invention may be prepared by nitration of a compound having th~ formula:
~,s~
- . ' ~ 6~

' ~ COX

OCH3 ) NRR' in which:
. X is a hydroxy or a Cl 5 alkoxy radical, and R and R' are hydrogen or an acyl radlical hydrogenating the formed 5-nitro compound, diazotizing the obtained 5-amino compound, then the amidifying of the so-obtained 4,5-azimido compound with the 1-allyl-2-aminomethyl- .
:: - pyrrolidine by direct reaction or by reaction of its reactive derivatives.
- 10 More specifically, the reaction can be achieved by j nitration of a lower alkyl ester of 2-methoxy-4-aminobenzoic -1 acid, by hydrogenation of the formed alkyl 2-methoxy-4-amino-5-nitrobenzoate, diazotization of the formed alkyl 2-methoxy-4,5-diaminobenzoate and amidation of the obtained alkyl 2-methoxy-4,5-azimidobenzoate with 1-allyl-2-aminomethyl-pyrrolidine.
In the first step of the above procqss preferably methyl 2-methoxy-4-aminobenzoate is employed. Other lower alkyl esters, such as ethyl, propyl, butyl or pentyl esters, however, can be used as well.
The hydrogenation of the nitro grou~ accordlng to the above process is achieved either by means of hydrogen in presence of catalysts, such as platinum, palladium or Raney- -nickel, or by nascent hydrogen with metals in presence of strong acids such as Fe/HCl or Sn/HCl or Zn/HCl, as well as by other suited hydrogenation agents.
- 2 - ~ .

,- - , .

1~366~t~

The thus obtained 4,5-diamino compound is then diazotized with a suitable diazotization agent such as NaN02/HCl or isoamyl nitrite whereby the corresponding 4,5-azimido compound is obtained.
The azimido compound is then amidated with l-allyl-2-aminomethylpyrrolidine. This reaction is carried out in the presence or absence of solvents. Such systems can be utilized as solvents which are inert with respect to t~e amidation reaction, such as alcohols, polyols, benzene, toluene, dioxane, chloroform, diethyleneglycol dimethylether. It is also possi-ble to use an excess of the amine used as reaction partner as solvent. It may be preferable to heat the reaction mixture during amidation, for example up to the boiling point of the above solvents.
According to the above synthetic route, the reaction can be conducted by starting from a lower alkyl ester of 2-methoxy-4-acylaminobenzoic acid. Instead of the acetyl group preferably employed for substituting the amino function in the 4th position of the above starting material also other easily 20 cleavable groups such as formyl, propionyl, butyryl, alkoxy- ;
carbonyl, phthaloyl or benzoyl can be used, a$ well as other suited cleavable groups.
The above reaction can also be achiqved in a way ~ -that the acyl group is cleaved before hydrogenation of the nitro group. The then obtained 4,5-diamino cqmpound can then be further reacted as described above.
If the acyl group is not a phthaloyl group, it can -also be cleaved after amidation.
..... .
An illustration of the process of the invention is given further by means of the following reaction scheme.
. : -: .... ; .,... . , . , ': ,~

C OOCH3 ~.~3f~6~i8 COOCH~5 ~ F 3 >
2 ~ 3 . N~2 COOC~
3 COOC~
2U J~ 3 ~ 3 ~ (NS 8aney) ~001 ,,NH ' ' ' ' 2 NH~

3 NO, N~ ~ ~r 3 . ~C~ N ~

.

~
COOCH3 C~ - NH - Cl(2~ J

NJ~ ~2N-CH2~ ~ ~O.,H~ ~ 2 ~J- N-~l C~2-cH~c~2 N ~ C~2 , . . . , , ' '. " .

. . ~ . .
... ... . .

.

1~36~i~18 According to the process of the invention, the reaction can be started from the 2-methoxy-4-~minobenzoic acid which can be nitrated, the formed 2-methoxy-41amino-5-nitro-benzoic acid hydrogenated, the formed 2-methoxy-4,5-diamino-benzoic acid diazotized, the thus obtained 2-methoxy-4,5-azimidobenzoic acid reacted either with a reactive derivate of l-allyl-2-aminomethylpyrrolidine or in form of one of its reactive derivates with l-allyl-2-aminomethylpyrrolidine. The N-(l'-allylpyrrolidinyl-2'-methyl)-2-methoxy-4,5-azimido-benzamide is obtained.
The same synthetic route can be applied to a 2-methoxy-4-acylaminobenzoic acid, as above defined.
. .
~; The starting material can be for example 2-methoxy-4-acetylaminobenzoic acid. This compound can bq nitrated, the ; thus obtained 2-methoxy-4-acetylamino-5-nitro~enzoic acid can be hydrogenated and diazotized in the manner explained above.
Finally the formed l-acetyl-5-carbohydroxy-6-methoxybenzotri-~:
azole can be reacted to the compound of the i~vention whereby either the above acid is reacted with a reactive derivate of 1-allyl-2-aminomethylpyrrolidine or the above amine is reacted with a reactive derivate of the acid and the reaction product is deacylated, possibly without prior isolation.
The deacylation can be effected prior to hydrogen- ~ ;
ation or diazotization. This operation method is necessary, for instance, in the case of 4-phthaloylamino substitutions.
In the above mentioned synthetic route the following products may be employed as reactive derivates of the amine: Reaction products of the amine with phosphorous chloride, phosphorous oxychloride, dialkyl - or diaryl or orthophenylene phosphites chlorinated, alkyl - or aryl dichlorinated phosphites or 1~
allylpyrrolidinyl-2-methylisothiocyanate. The above derivates ~366~8 can be reacted in situ or after prior isolation with the acid.
The invention, however, is not limited to the above reactive derivates.
The following compounds may be used as reactive derivates of the acid: reactive acid esters, for example cyanomethyl ester, methoxymethyl ester, substituted or not phenyl esters, acid halogenides, such as chlorides or bromides;
acid azides; symmetrical anhydrides; mixed anhydrides, for example formed with lower alkyl chloroformiates; hydrazides;
azolides, such as triazolides, tetrazolides, especially imidazolides; acid isocyanates. The invention, however is not limited to the afore-mentioned derivates.
Furthermore it is also possible to react the free acid and the free amine in presence of a condensation agent, for example a carbodiimide such as dicyclohexyl carbodiimide, silicium tetrachloride, phosphoric anhydride.
The compound obtained according to ~he process of the invention can be reacted if necessary with pharmaceutically acceptable inorganic or organic acids, such a$ hydrogen chloride, hydrogen bromide, sulfuric acid, phvsphoric acid, oxalic acid, acetic acid, tartric acid, citr~¢ acid, methane sulfonic acid, to an acid addition salt.
For therapeutical purposes the comp~und of the invention may be employed in form of a pharmaceutically acceptable acid addition salt along with pharmaceutically common auxiliary substances and/or dilution agents in the form of tablets, dragees, solutions for injection, sirups, or in any other suitable form.
Experiments relating to pharmacological tests prove -30 that the compound of the invention, referred to as compound A ~ ;
in the following, exhibits superior properties with respect to `~

-; ~ - . , . ~

1~366Q8 its antiemetic and kataleptic effectiveness at comparably low toxicities when compared with several partially commercialized benzamides known to be of excellent effectiveness. The follow-ing compounds are used as comparison materials:
1 - N,N-diethylaminoethyl-2-methoxy 4-amino-5-chlorobenzamide (compound B) commercialized under the generic name ~- "Metoclopramide"
2 - N-(l-ethylpyrrolidinyl-2-methyl)-2-methoxy-4,5-azimido-benzamide ~compound C) known from FR-PS 1 572 168, example 2. -The following experimental results are obtained:
A. Toxicity (DL50, mg/kg, i.v., 5 days, mice) Compound LD50 A 92.7 C 69.2 B. Antiemetic activity (DE50, s.c., dogs) Emesis induced by A B C
Apomorphine 5.4 26.8 14 ~/kg Hydergine 63 207 - ~I/kg Cubric sulfate0.99 0.92 - mg/kg Lanatoside 1.3 4.5 - mg/kg C. Therapeutical index LD50, i.v., M1ce J -_ _ _ ED50, s.c., Dogs Compound J

A 160 x 10 B 14 x 102 C 49 x 102 ` i(~366~8 D. Kataleptic activity (DE50, s.c., mg/kg) Compound ED50 A 10% at 200 mg/kg B 30.8 C 84.8 Thus the compound of the invention exhibits an essentially improved therapeutîcal index compared with the comparison compounds, at a reduced kataleptic activity.
. The above results have been confirmed in human therapy thereby the compound of the invention proved to be an effective antiemetic agent for the treatment Gf infants and grown-ups, especially in the therapy of symptoms of emesis of toxic or infectous syndromes, in pneumencephalography and in brain surgery, for naupathy and in the treatmqnt of postchemo-therapeutical, postradiotherapeutical and postsurgical emetic symptoms.
The invention is explained further by the following example although not been limited to it.

Step A: Methyl 2-methoxy-4-amino-5-nitrobenzoate 72.5 9 (0.4 mole) methyl 2-methoxy-4-aminobenzoate, 140 ml acetic acid and 126 9 acetic anhydride are brought into a 2 1. flask equipped with stirrer, thermometer and dropping funnel. The mixture is warmed to about 40C. during 30 minutes. 48 ml nitric acid (d - 1.49) are added drop by drop by means of the dropping funnel. The addition of nitric acid being terminated, stirring is continued for 2 hours at 40C.
Then the mixture is poured into 600 ml of a methanolic solution of sulfuric acid (0.4 mole). The mixture is then stirred. Then 1600 ml of water and ice are added. The formed crystals are filtered with suction. 55.2 9 (yield 61% methyl .~ .. ........ ... . . :

, ,- . . .

~3f~6~18 2-methoxy-4-amino-5-nitrobenzoate - m.p. 214C. -) are obtained.
Step B: Methyl 2-methoxy-4,5-diaminobenzoate 555 9 of methyl 2-methoxy-4-amino-5-nitrobenzoate~
2500 ml methanol, 300 9 Raney-nickel are brought into a 5 1.
autoclave. Hydrogen is applied with a pressure of 50 kg. The temperature rises to 50C. and is maintained during the entire absorption. After cooling nickel is removed by filtration and washed with methanol. The solvent is removed under reduced pressure. The formed crystals are washed two times with 600 ml water and dried at 50C. 305 g of methyl 2-methoxy-4,5-diaminobenzoate are obtained (yield 63.5%; m.p. - 139-140C).
; Step C: Methyl 2-methoxy-4,5-azimidobenzoate 294 9 (1.5 mole) of methyl 2-methoxy-4,5-diamino-benzoate, 2500 ml of water, 550 ml of hydrochloric acid -~
(d - 1.18) were introduced in a 5 1. flask equipped with stirrer, thermometer and dropping funnel. The mixture was cooled to 0-5C. and a solution of 108 9 of sodium nitrite in 500 ml of water was added dropwise. The mixt~re was heated to 35C. during 30 minutes, and then cooled. Th~ obtained crystals were filtered, washed three times with 300 ml of methylene chloride, and with water. After drying at 30C., 256 9 of methyl 2-methoxy-4,5-azimidobenzoate are obtained (yield 82.4%; m.p. 190-192C).
Step D: N-(l'-allylpyrrolidinyl-2'-methyl)-2-methoxy-4,5-azimidobenzamide chlorhvdrate . _ 621 9 methyl 2-methoxy-4,5-azimidobenzoate, 3 1.
anhydrous toluene and 425 9 of 1-allyl-2-aminomethylpyrroli-dine are brcught into a 6 1. -three-necked flask equipped with ' -sealed mechanical stirrer, thermometer and ascending refluxcondenser. The mixture is held under reflux conditions for five hours.

g _ :.

The mixture is cooled to 50C. after which 600 ml of - a solution of 350 9 hydrogen chloride in 1 1. ethanol areadded. The temperature raises to 70-80C. The mixture is cooled to 50C. after which the toluene layer is separated from an oily residue. --The latter is taken up in 3 1. methanol. The mixture is warmed until a complete dissolution is achieved.
~ This solution is filtered at its boiling temperature with 150 - g charcoal (3 S).
6 1. methyl ethyl ketone are added ~o the filtrate `- after which the mixture is cooled to 0C. The benzamide crystallizes slowly. It is filtered by suction and washed with 500 ml methyl ethyl ketone in two portions. After this it is dried at 50C. in a ventilated dryer.
687 9 of N~ allylpyrrolidinyl-2' methyl)-2-methoxy-4,5-azimidobenzamide chlorhydrate are obtained (yield 65g ) .
m.p. = 206-208C.
HCl % : theory : 10.38 found : 10.18 purity in non aqueous medium with HCl 04 : 99.5%.

Step A: Methyl 2-methoxy-4-acetylamino-5-nitrobenzoate 223 9 (1 mole) methyl 2-methoxy-4-acetylamino-benzoate, 350 ml acetic acid and 337 9 acetic anhydride are brought into a 2 1. flask equipped with stirrer, thermometer and dropping funnel. The mixture is warmed to about 40C.
whereby a clear solution is obtained. It is then cooled to 15-20C. after which 106 9 (1.5 mole) nitric acid (d = 1.49) are added drop by drop by means of the dropping funnel. The addition of nitric acid being terminated stirring is continued 1~366~8 for half an hour at 40C. Then the mixture is cooled and - poured into 5 1. water.
182 9 (yield 68%) methyl 2-methoxy-4-acetylamino-5-nitrobenzoate (m.p. 163-165C) are obtained.
Step B: Methyl 2-methoxy-4-acetylamino-5-aminobenzoate hydrochloride 1 kg methyl 2-methoxy-4-acetylamino-5-nitrobenzoate, - 3 1. ethyl acetate and 3 spoons Raney-nickel are brought into a 5 1. -autoclave. ~-The mixture is warmed to 75C with stirring. Then hydrogen gas is applied with a pressure of 50 kg. The '-~
reduction reaction starts quickly. For cooling purposes the -reaction vessel is ventilated. The temperature rises to 95C.
This temperature is maintained during the entire absorption.
The total absorption takes ten minutes. The hydrogen gas is recharged four to five times in equal manner 4ntil the absorption ceases.
The reaction is carried out within ~ne hour and fifteen minutes. After cooling nickel is removed by filtration and washed with 100 ml ethyl acetate. The filtrate is acidi-fied with 500 ml of a solution containing 350 g hydrogen chloride in 1000 ml ethanol. The hydrochloride crystall-izes.
It is filtered with suction at 15C. and washed with 500 ml ethyl acetate. It is dried in a ventilated dryer at 50C.
905 9 product (88%) with a melting point of 202-205C are obtained.
Step C: l-acetyl-5-carbomethoxy-6-methoxybenzotriazole ~ -14 1. water and 1920 g of methyl 2-methoxy-4-30 acetamino-5-aminobenzoate hydrochloride are brought into a ~- -20 1. -reaction vessel equipped with mechanical stirrer, ;
thermometer and dropping funnel and which is suitably moun~ed ' .". -1~366V8 to allow cooling by means of a cooling bath.
The hydrochloride is dissolved completely withstirring.
700 ml hydrochloric acid are added at once. There-after a solution of 490 g sodium nitrite in 1 1. water are added drop by drop within about one hour at a temperature between 25 and 30C. The azimido compound crystallizes -according to its formation.
The above addition terminated, stirring is continued for one hour at 25C.
The azimido compound is filtered by suction and washed several times with water. It is dried in a ventilated dryer at 30C.
1485 g (85%) product w~th a melting point of 114-115C. are obtained.
Step D: Meth~l 2-methoxv-4,5-azimidobenzoate 7.4 1. methanol and 1485 9 1-acetyl-5-carbomethoxy-6-methoxybenzotriazole are brought into a 20 1. -reaction vessel equipped with a sealed mechanical stirrer, ascending reflux cooler and dropping funnel.
The mixture is warmed with stirring to the reflux temperature. Then 460 ml hydrochloric acid are added.
Complete dissolution is observed. Then 100 g charcoal (3 S) are added, and reflux conditions are maintained for 20 minutes.
The charcoal is filtered off from the hot mixture.
The latter is cooled to 0C. whereby the azimido ester crystallizes. It is filtered by suction, washed several times with water and dried in a ventilated dryer at 50C.
780 g (63%) product are obtained.
The product is purified by dissolving 780 g azimido ester ~n a solution of 1 1. concentrated ammonia in 3.9 1.

- , ~36608 - water followed by the addition of 100 g charcoal. The mixture -is then allowed to stand for ten minutes after which it is filtered.
The filtrate is acidified with hydrochloric acid up ;
to pH _ 1. The azimido ester crystallizes. It is filtered by suction and washed several times with water. -` The moist product is again dissolved in a solution of 1 1. ammonia in 3.9 1. water and filtrated with 100 9.
charcoal.
` 10 The azimido compound is precipitated at a pH - 1 with hydrochloric acid. It is filtered with suction, washed with water and dried in a ventilated dryer at 50C. ~ `
742 9 (total yield 60%) of the colo4rless product with a melting point of 192C. are obtained.
Step E: N-(l'-allylpyrrolidinyl-2'-methyl)-2-methoxy-4,5-; azimidobenzamide chlorhydrate 621 9 methyl 2-methoxy-4,5-azimidobenzoate, 3 1. ~ -anhydrous toluene and 425 9 of 1-allyl-2-aminomethylpyrrolidine are brought into a 6 1. -three-necked flask equipped with sealed mechanical stirrer, thermometer and ascending reflux condenser. The mixture is held under reflux conditions for five hours.
The mixture is cooled to 50C. after which 600 ml of ` `~
a solution of 350 9 hydrogen chloride in 1 1. ethanol are added. The temperature raises to 70-80C. The mixture is cooled to 50C. after which the toluene layer is separated -from an oily residue.
The latter is taken up in 3 1. methanol. The .~-mixture is warmed until a complete dissolution is achleved.
This solution is filtered at its bo~ling temperature with 150 g charcoal (3 S).

:" ' . . . , , ~ , .

.
~ ~36~;Q~ -:

6 1. methyl ethyl ketone are added to the filtrate after which the mixture is cooled to 0C. The benzamide crystallizes slowly. It is filtered by suction and washed with 500 ml methyl ethyl ketone in two portions. After this it is dried at 50C. in a ventilated dryer.
687 9 of N-(l'-allylpyrrolidinyl-2'-methyl)-2-methoxy-4,5-azimidobenzamide chlorhydrate are obtained (yield 65X).
m.p. : 206-208C.
HCl X : theory 10.38 ~`-found 10.13 purity in non aqueous medium wlth HCl 04 : 99.5. ~ f Step A: 2-methoxy-4-amino-5-nitrobenzoic acid .~
. ~ In a same manner as in Step A of Example 1, 16.7 9 :' (0.1 mole) of 2-methoxy-4-aminobenzoic acid were nitrated.
13.8 9 of 2-methoxy-4-amino-5-nitrobenzoic acid were obtained (m.p. : 254C. - yield 64.9%).
Step B: 2-methoxy-4,5-dlaminobenzoic acid As described in Step B of Example 1, 28 g (0.13 mole) of 2-methoxy-4-amino-5-nitrobenzoic acid were hydrogenated and 19.8 9 of 2-methoxy-4,5-dlaminobenzoic acid were formed (yleld 83.6%).
Step C: 2-methoxy-4t5-azimidobenzoic acid 36.4 9 (0.2 mole) 2-methoxy-4,5-diaminobenzoic acid were treated as described in Step C of Example 1 by sodium nitrite in presence of hydrochloric acid. 31 9 of 2-methoxy-
4,5-azimidobenzoic acid are obtained (yield : 80.3g - m.p. :
245C).

~ -`\

1$36608 Step D: N~ allyl-2'-pyrrolidylmethyl)-2-methoxy-4,5-azimidobenzamide :
38.6 9 (0.2 mole) of 2-methoxy-4,5-azimidobenzoic - acid were dissolved in anhydrous toluene and 56 9 (0.4 mo1e) of l-allyl-2-aminomethylpyrrolidine were added. The mixture was heated to 50C. and then 42 9 (0.3 mole) of phosphoric anhydride are added. The mixture is warmed at reflux tempera-ture during 3 hours and then cooled to 80C. After adding water, the aqueous layer is alkalinizated. The crystals were filtered, washed with water and then dissolved in 450 ml of acetone. After crystallization, the product was filtered, washed and dried.
40.4 9 of N-(l'-allyl-2'-pyrrolidylmethyl)-2-methoxy-4,5-azimidobenzamide were obtained (yield : 65% - m.p. :
139C).

Step A: 2-methoxy-4-acetylamino-5-nitrobenzoic acid In the same manner as described in Step A of Example ;
2, 20.9 9 (0.1 mole) of 2-methoxy-4-acetylaminobenzoic acid were nitrated.
16.5 9 of 2-methoxy-4-acetylamino-5-nitrobenzolc acid were obtained (m.p. : 186-188C. - yleld : 64.9%).
Step B: 2-methoxy-4-acetylamino-5-aminobenzoic acid As described in Step B of Example 2, 32 g (0.13 mole) of 2-methoxy-4-acetylamino-5-nitrobenzoic acid were hydrogen-ated and 24.5 9 of 2-methoxy-4-acetylamlno-5-aminobenzoic acld were formed (yield : 84%).
Step C: l-acetyl-5-hydroxycarbonyl-6-methoxybenzotriazole ;
;
8.7 9 (0.039 mole) of 2-methoxy-4-acetylamino-5-aminobenzoic acid were treated, as described in Step C of Example 2, by sodium nitrite in presence of hydrochlorlc acid.
.-. ,': .

` ~ 10366~)8 7.3 9 of 1-acetyl-5-hydroxycarbonyl-6-methoxybenzo-triazole were obtained (m.p. : 208-212C. - yield : 79.6%).
Step D: l-acetyl-5-chlorocarbonyl-6-methoxybenzotriazole 4.7 9 of 1-acetyl-5-hydroxycarbonyl-6-methoxybenzo-triazole, 16.5 ml of thionyl chloride, 11 ml of chloroform are introduced in a 250 ml flask. The mixture is heated to the reflux temperature during 30 minutes. After cooling, the solvents are removed under reduced pressure.
4.7 9 of 1-acetyl-5-chlorocarbonyl-6-methoxybenzo-~` 10 triazole are obtained (yield : 92.7% - m.p. : 170C).
Step E: N-(l'-allyl-2'-pyrrolidylmethyl)-2-methoxy-4,5-azimidobenzamide chlorhydrate ~, 2.2 9 (0.016 mole) of 1-allyl-2-aminomethylpyrroli-dine, 28 ml of methyl-ethylcetone are introduced in a 250 ml flask. Then 3.8 g (0.015 mole) of 1-acetyl-5-chlorocarbonyl-6-methoxybenzotriazole were added. The mixture was allowed to ~i stand overnight, the solvent was removed under reduced : ~ -pressure. 5 ml of hydrochloric acid (d : 1.18) and 28 ml of ethyl alcohol were added and the mixture was heated to the reflux temperature during 30 minutes. After cooling, the solvent was removed under reduced pressure, and the residue was dissolved in boiling dimethyl formamide. The mixture is filtered, and after cooling, the benzamide crystallizes. The crystals were filtered by suction, washed with some dimethyl formamide, then with tetrahydrofuran, and were dried at 50C.
3.2 9 of N-(l'-ally1-2'-pyrrolidylmethyl)-2-methoxy-4,5-azimidobenzamide chlorhydrate were obtained (yield :
60~7X).
m.p. : 206C.
HCl % : theory 10.38 found 10.27.

Claims (28)

The embodiments of the invention in which an exclu-sive property or privilege is claimed are defined as follows:
1. The process for preparing the N-(1'-allyl-pyrrolidinyl-2'-methyl)-2-methoxy-4,5-azimidobenzaamide which comprises reacting a compound of the formula:

wherein:
X is hydrogen, lower alkoxy or chloro, and R is hydrogen or acyl, with 1-allyl-2-aminomethyl-pyrrolidine.
2. The process of Claim 1, wherein X is lower alkyl and R is hydrogen.
3. The process of Claim 1, wherein X is hydrogen and R is hydrogen.
4. The process of Claim 1, wherein X is chloro and R is acyl.
5. The process of Claim 1, wherein the starting compound where X is lower alkoxy or hydrogen and R is hydrogen is obtained by the diazotization of 2-methoxy-4,5-diamino-benzoic acid or a lower alkyl ester thereof.
6. The process of Claim 5, wherein the 2-methoxy-4,5-diaminobenzoic acid or lower alkyl ester thereof is obtained by nitrating 2-methoxy-4-aminobenzoic acid or the lower alkyl ester thereof to form the 2-methoxy-4-amino-5-nitrobenzoic acid or the lower alkyl ester thereof, and submitting the latter compound to hydrogenation to form the desired 2-methoxy-4,5-diaminobenzoic acid or the lower alkyl ester thereof.
7. The process of Claim 1, wherein the starting compound where X is lower alkoxy or hydrogen and R is lower acyl is obtained by the hydrolysis of the 1-acetyl-5-carbo-methoxy-6-methoxybenzotriazole.
8. The process of Claim 7, wherein the 1-acetyl-5-carbomethoxy-6-methoxybenzotriazole is obtained by nitrating the lower alkyl 2-methoxy-4-acetylaminobenzoate to form the lower alkyl 2-methoxy-4-acetylamino-5-nitrobenzoate, hydrogen-ating the latter to form the lower alkyl 2-methoxy-4-acetyl-amino-5-aminobenzoate and diazotizing the latter compound.
9. The process of Claim 1, wherein the starting compound where X is chloro and R is lower acyl is obtained by diazotizing the 1-lower acyl-5-hydroxycarbonyl-6-methoxybenzo-triazole followed by chlorination of the resulting compound to yield the 1-lower acyl-5-chlorocarbonyl-6-methoxybenzotriazole.
10. The process of Claim 1, wherein methyl 2-methoxy-4,5-azimidobenzoate is reacted with 1-allyl-2-aminomethyl-pyrrolidine.
11. The process of Claim 10, wherein the starting methyl 2-methoxy-4,5-azimidobenzoate is obtained by diazoti-zation of methyl 2-methoxy-4,5-diaminobenzoate.
12. The process of Claim 1, wherein the methyl 2-methoxy-4,5-diaminobenzoate is obtained by nitrating methyl 2-methoxy-4-aminobenzoate to form the methyl 2-methoxy-4-amino-5-nitrobenzoate, and hydrogenating the latter compound.
13. The process of Claim 1, wherein 2-methoxy-4,5-azimidobenzoate is reacted with 1-allyl-2-aminomethyl-pyrrolidine.
14. The process of Claim 13, wherein the 2-methoxy-4,5-azimidobenzoate is obtained by diazotization of 2-methoxy-4,5-diaminobenzoic acid.
15. The process of Claim 14, wherein the 2-methoxy-4,5-azimidobenzoate is obtained by nitrating 2-methoxy-4-aminobenzoic acid to form the 2-methoxy-4,5-diaminobenzoic acid and hydrogenating the latter compound.
16. The process of Claim 1, wherein methyl 2-methoxy-4,5-azimidobenzoate is reacted with 1-allyl-2-aminomethyl-pyrrolidine.
17. The process of Claim 16, wherein the methyl 2-methoxy-4,5-azimidobenzoate is obtained by hydrolyzing 1-acetyl-5-carbomethoxy-6-methoxybenzotriazole.
18. The process of Claim 17, wherein the 1-acetyl-5-carbomethoxy-6-methoxybenzotriazole is obtained by nitrating the methyl 2-methoxy-4-acetylaminobenzoate to form the methyl 2-methoxy-4-acetylamino-5-nitrobenzoate, hydrogenating the latter to form the methyl 2-methoxy-4-acetylamino-5-amino-benzoate and diazotizing the latter compound.
19. The process of Claim 1, wherein 1-acetyl-5-chlorocarbony1-6-methoxybenzotriazole is reacted with 1-allyl-2-aminomethylpyrrolidine.
20. The process of Claim 1, wherein the starting 1-acetyl-5-chlorocarbonyl-6-methoxybenzotriazole is obtained by the chlorination of the 1-acetyl-5-hydroxycarbonyl-6-methoxy-benzotriazole.
21. The process of Claim 20, wherein the 1-acety1-5-hydroxycarbonyl-6-methoxybenzotriazole is obtained by nitrating the 2-methoxy-4-acetylaminobenzoic acid to form the 2-methoxy-4-acetylamino-5-nitrobenzoic acid, hydrogenating the latter compound to form the 2-methoxy-4-acetylamino-5-amino-benzoic acid, diazotizing the latter compound to form the 1-acetyl-5-hydroxycarbonyl-6-methoxybenzotriazole.
22. The N-(1'-allylpyrrolidinyl-2'-methyl)-2-methoxy-4,5-azimidobenzamide, when prepared by the process defined in Claim 1, 2 or 3 or by an obvious chemical equivalent.
23. The N-(1'-allylpyrrolidinyl-2'-methyl)-2-methoxy-4,5-azimidobenzamide, when prepared by the process defined in Claim 4, 5 or 6 or by an obvious chemical equivalent.
24. The N-(1'-allylpyrrolidinyl-2'-methyl)-2-methoxy-4,5-azimidobenzamide, when prepared by the process defined in Claim 7, 8 or 9 or by an obvious chemical equivalent.
25. The N-(1'-allylpyrrolidinyl-2'-methyl)-2-methoxy-4,5-azimidobenzamide, when prepared by the process defined in Claim 10, 11 or 12 or by an obvious chemical equivalent.
26. The N-(1'-allylpyrrolidinyl-2'-methyl)-2-methoxy-4,5-azimidobenzamide, when prepared by the process defined in Claim 13, 14 or 15 or by an obvious chemical equivalent.
27. The N-(1'-allylpyrrolidinyl-2'-methyl)-2-methoxy-4,5-azimidobenzamide, when prepared by the process defined in Claim 16, 17 or 18 or by an obvious chemical equivalent.
28. The N-(1'-allylpyrrolidinyl-2'-methyl)-2-methoxy-4,5-azimidobenzamide, when prepared by the process defined in Claim 19, 20 or 21 or by an obvious chemical equivalent.
CA221,531A 1975-01-11 1975-03-07 N-(1'-allylpyrrolidinyl-2'-methyl)-2-methoxy-4,5-azimidobenzamide, salts and preparation thereof Expired CA1036608A (en)

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